Tricyclic inhibitors of protein farnesyltransferase

ABSTRACT

Compounds of formula I ##STR1## wherein X is N or C--R 9 , Y is N--R 10 , CH 2 , O, S, SO, SO 2 , C═O or CH--OH, 
     R is H or alkyl, 
     R 1  is heteroaryl, 
     n is 1-5, and 
     R 2  -R 10  are H or various substituents, 
     are useful as inhibitors of protein farnesyl transferase and for the treatment of proliferative diseases including cancer, restenosis and psoriasis, and as antiviral agents.

This application claims benefit of provisional application Ser. No.60/000,913 filed Jun. 16, 1995.

BACKGROUND OF THE INVENTION

The present invention relates to novel tricyclic compounds useful aspharmaceutical agents, to methods for their production, topharmaceutical compositions which include these compounds and apharmaceutically acceptable carrier, and to pharmaceutical methods oftreatment. The novel compounds of the present invention inhibitfarnesyltransferase enzyme which activates ras proteins which in turnactivate cellular division. More particularly, the novel compounds ofthe present invention are useful in the treatment of proliferativediseases such as, for example, cancer, restenosis, and psoriasis, and asantiviral agents.

Ras protein (or p21) has been examined extensively because mutant formsare found in 20% of most types of human cancer and greater than 50% ofcolon and pancreatic carcinomas (Gibbs J. B., Cell, 65:1 (1991),Cartwright T., et al., Chimica. Oggi., 10:26 (1992)). These mutant rasproteins are deficient in the capability for feedback regulation that ispresent in native ras and this deficiency is associated with theironcogenic action since the ability to stimulate normal cell division cannot be controlled by the normal endogenous regulatory cofactors. Therecent discovery that the transforming activity of mutant ras iscritically dependent on post-translational modifications (Gibbs J., etal., Microbiol. Rev., 53:171 (1989)) has unveiled an important aspect ofras function and identified novel prospects for cancer therapy.

In addition to cancer, there are other conditions of uncontrolledcellular proliferation that may be related to excessive expressionand/or function of native ras proteins. Post-surgical vascularrestenosis is such a condition. The use of various surgicalrevascularization techniques such as saphenous vein bypass grafting,endarterectomy and transluminal coronary angioplasty is oftenaccompanied by complications due to uncontrolled growth of neointimaltissue, known as restenosis. The biochemical causes of restenosis arepoorly understood and numerous growth factors and protooncogenes havebeen implicated (Naftilan A. J., et al., Hypertension, 13:706 (1989) andJ. Clin. Invest., 83:1419; Gibbons G. H., et al., Hypertension, 14:358(1989); Satoh T., et al., Mollec. Cell. Biol., 13:3706 (1993)). The factthat ras proteins are known to be involved in cell division processesmakes them a candidate for intervention in many situations where cellsare dividing uncontrollably. In direct analogy to the inhibition ofmutant ras related cancer, blockade of ras dependant processes has thepotential to reduce or eliminate the inappropriate tissue proliferationassociated with restenosis, particularly in those instances where normalras expression and/or function is exaggerated by growth stimulatoryfactors.

Ras functioning is dependent upon the modification of the proteins inorder to associate with the inner face of plasma membranes. Unlike othermembrane-associated proteins, ras proteins lack conventionaltransmembrane or hydrophobic sequences and are initially synthesized ina cytosol soluble form. Ras protein membrane association is triggered bya series of post-translational processing steps that are signaled by acarboxyl terminal amino acid consensus sequence that is recognized byprotein farnesyltransferase (PFT). This consensus sequence consists of acysteine residue located four amino acids from the carboxyl terminus,followed by two lipophilic amino acids and the C-terminal residue. Thesulfhydryl group of the cysteine residue is alkylated byfarnesylpyrophosphate in a reaction that is catalyzed by proteinfarnesyltransferase. Following prenylation, the C-terminal three aminoacids are cleaved by an endoprotease and the newly exposedalpha-carboxyl group of the prenylated cysteine is methylated by amethyl transferase. The enzymatic processing of ras proteins that beginswith farnesylation enables the protein to associate with the cellmembrane. Mutational analysis of oncogenic ras proteins indicate thatthese post-translational modifications are essential for transformingactivity. Replacement of the consensus sequence cysteine residue withother amino acids gives a ras protein that is no longer farnesylated,fails to migrate to the cell membrane and lacks the ability to stimulatecell proliferation (Hancock J. F., et al., Cell, 57:1167 (1989), SchaferW. R., et al., Science, 245:379 (1989), Casey P. J., Proc. Natl. Acad.Sci. USA, 86:8323 (1989)).

Recently, protein farnesyltransferases (PFTs, also referred to asfarnesyl proteintransferases (FPTs) have been identified and a specificPFT from rat brain was purified to homogeneity (Reiss Y., et al., Bioch.Soc. Trans., 20:487-88 (1992)). The enzyme was characterized as aheterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit(46 kDa), both of which are required for catalytic activity. High levelexpression of mammalian PFT in a baculovirus system and purification ofthe recombinant enzyme in active form has also been accomplished (ChenW.-J., et al., J. Biol. Chem., 268:9675 (1993)).

In light of the foregoing, the discovery that the function of oncogenicras proteins is critically dependent on their post-translationalprocessing provides a means of cancer chemotherapy through inhibition ofthe processing enzymes. The identification and isolation of a proteinfarnesyltransferase that catalyzes the addition of a farnesyl group toras proteins provides a promising target for such intervention.Recently, it has been determined that prototypical inhibitors of PFT caninhibit ras processing and reverse cancerous morphology in tumor cellmodels (Kohl N. E., et al., Science, 260:1934 (1993), James G. L., etal., Science, 260:1937 (1993), Garcia A. M., et al., J. Biol. Chem.,268:18415 (1993)). Furthermore, Blaskovich M., et al., "ProceedingsEighty-Sixth Annual Meeting American Association For Cancer Research,"Mar. 18-22, 1995, Toronto, Ontario, Canada, Vol. 86, March 1995,Abstract 2578, disclosed a series of tetrapeptide inhibitors offarnesyltransferase which inhibited growth of tumor cells in nude mice.

Nagasu T., et al., "Proceedings Eighty-Sixth Annual Meeting AmericanAssociation For Cancer Research," Mar. 18-22, 1995, Toronto, Ontario,Canada, Vol. 86, March 1995, Abstract 2615, disclosed a peptidomimeticinhibitor, B956, of farnesyltransferase which inhibits growth of humantumor xenografts in nude mice. Inhibition of tumor growth is correlatedwith inhibition of ras processing.

Thus, it is possible to prevent or delay the onset of cellularproliferation in cancers that exhibit mutant ras proteins by blockingPFT. By analogous logic, inhibition of PFT would provide a potentialmeans for controlling cellular proliferation associated with restenosis,especially in those cases wherein the expression and/or function ofnative ras is overstimulated.

PCT Published Patent Application WO91/16340 discloses cysteinecontaining tetrapeptide inhibitors of PFT of the Formula CAAX.

PCT Published Patent Application WO94/26723 discloses a series ofbenzodiazepine derivatives as inhibitors of rasfarnesyl:proteintransferase.

British Published Patent Application UK 980,853 disclosed compounds ofthe formula: ##STR2## and acid addition salts and quaternary ammoniumderivatives thereof, in which:

Z represents a sulphur atom or a sulphoxide group (--SO--) or an aminogroup of the formula --(N--R₁)--, wherein R₁ represents a hydrogen atomor a protecting group, e.g., an acyl or a benzyl group, or an alkyl oralkenyl group containing up to 5 carbon atoms;

R₂ and R₃, which may be the same or different, represent hydrogen atoms,or alkyl or alkenyl groups containing up to 5 carbon atoms, aminogroups, monoalkylamino or dialkylamino groups, monoalkylaminoalkyl ordialkylaminoalkyl groups or monocyclic aryl or aralkyl groups, whicharyl or aralkyl groups may be substitued with halogen atoms,trifluoromethyl groups, hydroxy groups or alkyl groups, alkoxy groups oralkylmercapto groups containing from 1 to 3 carbon atoms, or maytogether with the adjacent nitrogen atom form a cycloalkylamino groupwhich may contain further heteroatoms, which heteroatoms, if nitrogen,may carry hydrogen atoms, alkyl groups, hydroxyalkyl groups oralkoxyalkyl groups, and R₄ and R₅, which may be the same or different,represent hydrogen or halogen atoms, or trifluoromethyl groups orhydroxy groups or alkyl, alkoxy or alkylmercapto groups containing from1 to 3 carbon atoms for use as analgesics, chemotherapeutic agents,antihistamines, and as antiphlogistic and antioedemic agents.

British Published Patent Application UK 1,177,956 discloses a process ofpreparing compounds of the formula: ##STR3## wherein X is an oxygen orsulfur; one of R₁ and R₂ is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,halogen or trifluoromethyl, and the other of R₁ and R₂ is hydrogen, (C₁-C₆)alkoxy or halogen; Y is hydroxy, amino, (C₁ -C₆)alkylamino, di-(C₁-C₆)alkylamino, 1-piperazinyl, 4-(C₁ -C₆)-alkyl-1-piperazinyl,4-hydroxy-(C₁ -C₆)-alkyl-1-piperazinyl, pyrrolidino, (C₁-C₆)alkyl-pyrrolidino, piperidino, (C₁ -C₆)alkyl piperidino, morpholino,or (C₁ -C₆)alkylmorpholino; R is (C₁ -C₆)alkyl; n is 2, 3, or 4; or the##STR4## group taken together represents 1-piperazinyl, 4-(C₁-C₆)-alkyl-1-piperazinyl, or 4-hydroxy-(C₁ -C₆)-alkyl-1-piperazinyl.These compounds were disclosed as having activity as tranquilizers andin some instances as antidepressants.

U.S. Pat. No. 3,539,573 discloses compounds of general Formula A:##STR5## wherein Z denotes a member of the class consisting of bivalentsulfur, imino, and lower alkyl imino; R₁ is a member of the classconsisting of hydrogen and alkyl with 1 to 5 carbon atoms, and R₂ is amember of the class consisting of hydrogen, alkyl having from 1 to 5carbon atoms, phenyl, R₅ -substituted phenyl, aminoalkyl having from 1to 5 carbon atoms, lower alkylated aminoalkyl having from 2 to 8 carbonatoms, amino, and lower alkylated amino; or R₁ and R₂ together with Nform a member of the class consisting of 1-pyrrolidinyl, piperidino,morpholino, thiomorpholino, 1-piperazinyl, 4-(loweralkyl)-1-piperazinyl, 4-(lower hydroxyalkyl)-1-piperazinyl, and 4-(loweralkoxy-lower alkyl)-1-piperazinyl; and R₃, R₄, and R₅ are members of theclass consisting of hydrogen, halogen, hydroxy, trifluoromethyl, loweralkyl, lower alkoxy, and lower alkylthio; and (B) 11-basic substituteddibenzodiazepines and dibenzothiazepines having the general Formula B:##STR6## wherein Z' denotes a member of the group consisting of sulfur,sulphinyl, and imino; R'₁ represents a member of the group consisting ofhydrogen, allyl, alkyl containing not more than 3 carbon atoms,hydroxyalkyl containing not more than 3 carbon atoms, alkoxyalkylcontaining not more than 6 carbon atoms, and alkoyloxyalkyl containingnot more than 6 carbon atoms; and R'₂ is a member of the groupconsisting of nitro, amino, aminosulphonyl of the formula --SO₂ NR'₃ R'₄wherein R'₃ and R'₄ are the same or different members of the groupconsisting of hydrogen and methyl, alkylsulphinyl of the formula --SOR'₅wherein R'₅ denotes alkyl with not more than 3 carbon atoms, andalkylsulphonyl of the formula --SO₂ R'₅ wherein R'₅ denotes alkyl withnot more than 3 carbon atoms; and (C) the nontoxic pharmaceuticallyacceptable acid-addition salts of (A) and (B).

These compounds are disclosed to be used as neuroplegics, neuroleptics,neuroleptic antidepressants, antiemetics, analgesics, sedatives,parasympathicolytics, and antihistaminics.

European Published Patent Application 0461869 discloses cysteinecontaining tetrapeptide inhibitors of PFT of the Formula Cys-Aaa¹ -Aaa²-Xaa.

European Published Patent Application 0520823 discloses cysteinecontaining tetrapeptide inhibitors of PFT of the Formula Cys-Xaa¹ -dXaa²-Xaa³.

European Published Patent Application 0523873 discloses cysteinecontaining tetrapeptide inhibitors of PFT of the Formula Cys-Xaa¹ -Xaa²-Xaa³.

European Published Patent Application 0528486 discloses cysteinecontaining tetrapeptide amides inhibitors of PFT of the Formula Cys-Xaa¹-Xaa² -Xaa³ -NRR¹.

European Published Patent Application 0535730 disclosespseudotetrapeptide inhibitors of PFT of the following two formulas:##STR7##

Copending U.S. patent application Ser. No. 08/268,364 discloses a seriesof histidine and homohistidine derivatives as inhibitors of proteinfarnesyltransferase.

Compounds disclosed in the above references do not disclose or suggestthe novel combination of structural variations found in the presentinvention described hereinafter.

We have surprisingly and unexpectedly found that a series of tricycliccompounds are inhibitors of farnesyltransferase and thus useful asagents for the treatment of proliferative diseases such as, for example,cancer, restenosis, and psoriasis, and as antiviral agents.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR8##wherein X is C--R⁹, wherein R⁹ is as defined herein after or N; Y is##STR9## wherein R¹⁰ is hydrogen, alkyl, or substituted alkyl whereinthe substituent on the alkyl group is selected from the group consistingof:

OR¹¹ wherein R¹¹ is hydrogen, or alkyl,

SR¹¹ wherein R¹¹ is as defined above,

CO₂ R¹² wherein R¹² is hydrogen, alkyl, or benzyl, ##STR10## wherein R¹³and R¹⁴ are independently the same or different and each is hydrogen,alkyl, or

R¹³ and R¹⁴ are taken together with N to form a 5- or 6-membered ringoptionally containing a heteroatom selected from the group consisting ofN, S, and O or ##STR11## wherein R¹³ and R¹⁴ are as defined above, --CH₂--, --O--, --S(O)_(m) -- wherein m is zero or an integer of 1 or 2,##STR12## or R is hydrogen, or alkyl;

n is an integer of 1 to 5;

R¹ is heteroaryl;

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are each independently the same ordifferent and each is hydrogen, NO₂, ##STR13## wherein R¹³ and R¹⁴ areas defined above, ##STR14## wherein R¹⁵ is hydrogen, alkyl, or aryl, CO₂R¹² wherein R¹² is as defined above, ##STR15## wherein R¹³ and R¹⁴ areas defined above, ##STR16## wherein R¹⁶ is alkyl, aryl, or arylalkyl,halogen, CN, OH, SR¹⁷ wherein R¹⁷ is hydrogen, or alkyl, SO alkyl, SO₂alkyl, alkoxy, benzyloxy, alkyl, or

substituted alkyl wherein the substituents on the alkyl group are asdefined above;

with the proviso that at least two of R², R³, R⁴, or R⁹ are hydrogen andat least one of R⁵, R⁶, R⁷, or R⁸ is hydrogen;

and corresponding isomers thereof;

or a pharmaceutically acceptable salt thereof.

As inhibitors of farnesyltransferase, the compounds of Formula I areantiproliferative agents. Thus, they are useful for the treatment ofcancer, restenosis, and psoriasis, and as antiviral agents.Additionally, a compound of Formula I may be combined with otherconventional anti-cancer agents such as, for example, cisplatin.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.Finally, the present invention is directed to methods for production ofa compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon radical having from 1 to 6 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

"Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbonatoms as defined above for "alkyl".

The term "aryl" means an aromatic radical which is a phenyl group, anaphthyl group, a phenyl group substituted by 1 to 4 substituentsselected from alkyl as defined above, alkoxy as defined above,thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino,alkylamino as defined above for alkyl, dialkylamino as defined foralkyl, N-acetylamino, cyano or nitro, or a naphthyl group substituted by1 to 4 substituents as defined above for a phenyl group substituted by 1to 4 substituents.

The term "heteroaryl" means a heteroaromatic radical which is 2- or3-thienyl; 2- or 3-furanyl; 1-, 2- or 3-pyrrolyl; 1-, 2-, 4-, or5-imidazolyl; 1-, 3-, 4-, or 5-pyrazolyl; 2-, 4-, or 5-thiazolyl; 3-,4-, or 5-isothiazolyl; 2-, 4-, or 5-oxazolyl; 3-, 4-, or 5-isoxazolyl;1-, 3-, or 5-1,2,4-triazolyl; 1-, 2-, 4-, or 5-1,2,3-triazolyl; 1- or5-tetrazolyl; 4-, or 5-1,2,3-oxadiazolyl; 3-, or 5-1,2,4-oxadiazolyl;2-1,3,4-oxadiazolyl; 2-1,3,4-thiadiazoyl; 2-1,3,5-triazinyl;3-pyridinyl; 3-, 4-, or 5-pyridazinyl; 2-pyrazinyl; 2-, 4-, or5-pyrimidinyl; unsubstituted or substituted by 1 to 2 substituentsselected from NH₂, OH, SH, halogen as defined hereinafter, alkyl asdefined above, or alkoxy as defined above.

The term "arylalkyl" means an aromatic radical attached to an alkylradical wherein aryl and alkyl are as defined above for example benzyl,fluorenylmethyl, and the like.

"Halogen" is fluorine, chlorine, bromine, or iodine.

The compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,"Pharmaceutical Salts," J. of Pharma. Sci., 66:1 (1977)).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., et al., "Pharmaceutical Salts," J. ofPharma. Sci., 66:1 (1977)).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

A preferred compound of Formula I is one wherein R¹ is a heteroarylradical selected from the group consisting of:

2- or 3-thienyl;

2- or 3-furanyl;

1-, 2- or 3-pyrrolyl;

1-, 2-, 4-, or 5-imidazolyl;

1-, 3-, 4-, or 5-pyrazolyl;

2-, 4-, or 5-thiazolyl;

3-, 4-, or 5-isothiazolyl;

2-, 4-, or 5-oxazolyl;

3-, 4-, or 5-isoxazolyl;

1-, 3-, or 5-1,2,4-triazolyl;

1-, 2-, 4- or 5-1,2,3-triazolyl;

1- or 5-tetrazolyl;

4- or 5-1,2,3-oxadiazolyl;

3- or 5-1,2,4-oxadiazolyl;

2-1,3,4-oxadiazolyl;

2-1,3,4-thiadiazoyl;

2-1,3,5-triazinyl;

3-pyridinyl;

3-, 4-, or 5-pyridazinyl;

2-pyrazinyl; and

2-, 4-, or 5-pyrimidinyl; or

optionally, the heteroaryl radical is substituted with a substituentselected from the group consisting of:

NH₂, OH, SH, halogen, alkyl, or alkoxy.

A more preferred compound of Formula I is one wherein

Y is --NH-- ##STR17## --O--, --S--, or --SO₂ --; n is an integer of 1 to5;

R¹ is a heteroaryl radical selected from the group consisting of:

1-, 2-, or 4-imidazolyl, 3-pyridinyl, 1-, 3-, or 5-1,2,4-triazolyl,5-thiazolyl, or 5-oxazolyl;

R³ and R⁴ are hydrogen or alkoxy;

R⁶ and R⁷ are hydrogen, halogen, mercaptomethyl, hydroxymethyl, alkoxy,alkyl, or benzyloxy.

Particularly valuable is a compound selected from the group consistingof:

(8-Chloro-5H-dibenzo b,e! 1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(8-Chloro-5H-dibenzo b,e! 1,4!diazepin-11-yl)-2-(3H-imidazol-4-yl)-ethyl!-amine;

(8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(2-pyridin-3-yl-ethyl)-amine;

(8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(2-imidazol-1-yl-ethyl)-amine;

(8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(3-imidazol-1-yl-propyl)-amine;

(7-Chloro-5H-dibenzo b,e! 1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(5H-Dibenzo b,e! 1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine;

(8-Methyl-5H-dibenzo b,e! 1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(8-Methoxy-5H-dibenzo b,e! 1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(8-Bromo-5H-dibenzo b,e! 1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(7,8-Dichloro-5H-dibenzo b,e!1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(8-Benzyloxy-5H-dibenzo b,e!1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine;

(7,8-Dichloro-2,3-dimethoxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine;

(11H-Benzo b!pyrido 2,3-e! 1,4!diazepin-5-yl)pyridin-3-ylmethyl-amine;

(8-Chloro-5-methyl-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine;

(8-Chloro-dibenzo b,f! 1,4!thiazepin-11-yl)pyridin-3-ylmethyl-amine;

(8-Chloro-5,5-dioxo-5H-5λ⁶ -dibenzo b,f!1,4!thiazepin-11-yl)-pyridin-3-ylmethyl-amine; and

(8-Chloro-dibenzo b,f! 1,4!oxazepin-11-yl)pyridin-3-ylmethyl-amine; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.

The compounds of Formula I are valuable inhibitors of the enzymefarnesyltransferase.

The protein:farnesyltransferase (PFT) or farnesyl protein transferase(FPT) inhibitory activity of compounds of Formula I was assayed in HEPESbuffer (pH 7.4) containing 5 mM potassium phosphate and 20 μM ZnCl₂. Thesolution also contained 7 mM DTT, 1.2 mM MgCl₂, 0.1 mM leupeptin, 0.1 mMpepstatin, and 0.2 mM phenylmethylsulfonyl fluoride. Assays wereperformed in 96 well plates (Wallec) and employed solutions composed ofvarying concentrations of a compound of Formula I in 100% DMSO. Uponaddition of both substrates, radiolabeled farnesyl pyrophosphate ( 1-³H!, specific activity 15-30 Ci/mmol, final concentration 0.12 μM) and(biotinyl)-Ahe-Tyr-Lys-Cys-Val-Ile-Met peptide (final concentration 0.2μM), the enzyme reaction was started by addition of 40-fold purified ratbrain farnesyl protein transferase. After incubation at 37° for 30minutes, the reaction was terminated by diluting the reaction 2.5-foldwith a stop buffer containing 1.5M magnesium acetate, 0.2M H₃ PO₄, 0.5%BSA, and strepavidin beads (Amersham) at a concentration of 1.3 mg/mL.After allowing the plate to settle for 30 minutes at room temperature,radioactivity was quantitated on a microBeta counter (Model 1450,Wallec). Compounds of Formula I show IC₅₀ values of 0.8 to 60 μM in thisassay and are thus valuable inhibitors of protein:farnesyltransferaseenzyme which may be used in the medical treatment of tissueproliferative diseases, including cancer and restenosis. The assay wasalso carried out without 5 mM potassium phosphate.

Gel Shift Assay

Twenty-four hours after planting 2×10⁶ ras-transformed cells pertreatment condition, the farnesylation inhibitor is added at varyingconcentrations. Following an 18-hour incubation period, cells are lysedin phosphate-buffered saline containing 1% Triton X-100, 0.5% sodiumdeoxycholate, and 0.1% SDS, pH 7.4 in the presence of several proteaseinhibitors (PMSF, antipain, leupeptin, pepstatin A, and aprotinin all at1 μg/mL). Ras protein is immunoprecipitated from the supernatants by theaddition of 3 μg v-H-ras Ab-2 (Y13-259 antibody from oncogene Science).After overnight immunoprecipitation, 30 μL of a 50% protein G-Sepharoseslurry (Pharmacia) is added followed by 45-minute incubation. Pelletsare resuspended in 2× tris-glycine loading buffer (Novex) containing 5%B-mercaptoethanol and then denatured by 5 minutes boiling prior toelectrophoresis on 14% Tris-glycine SDS gels. Using Western transfertechniques, proteins are transferred to nitrocellulose membranesfollowed by blocking in blocking buffer. Upon overnight incubation withprimary antibody (pan-ras Ab-2 from Oncogene Science), an antimouse HRPconjugate secondary antibody (Amersham) is employed for detection of theras protein. Blots are developed using ECL techniques (Amersham).

Antiproliferation Assay

H-Ras-transformed cells (total of 1×10⁵ cells per treatment condition)are planted into T-25 flasks. Forty-eight hours later, the farnesylationinhibitor is, added at varying concentrations. After 72-hour exposure,cells are trypsinized and viability quantitated by counting the numberof trypan blue-excluding cells on a hemacytometer.

The data in Table 1 show farnesyl protein transferase inhibitoryactivity, activity in the gel shift assay against ras protein, andinhibition of cell growth of selected compounds of Formula I.

                                      TABLE 1    __________________________________________________________________________    Biological Activity of Compounds of Formula I                                     Cell                     Farnesyl Protein                                     Growth                     Transferase Inhibition                                Gel Shift                                     Inhibition                          Hepes/                                Minimum                                     H-Ras-                     Hepes                          5 mM PO.sub.4.sup.-3                                Effective                                     transformed    Example         Compound    IC.sub.50 (μM)                          IC.sub.50 (μM)                                Dose (μM)                                     Cells    __________________________________________________________________________    1    (8-Chloro-5H-dibenzo                     3.7  5.0   50   11          b,e! 1,4!diazepin-11-         yl)pyridin-3-ylmethyl-         amine    2    (8-Chloro-5H-dibenzo                     2.4  3.0   25   4          b,e! 1,4!-diazepin-11-         yl)- 2-(3H-imidazol-4-         yl)-ethyl!-amine    3    (8-Chloro-5H-dibenzo                     36   57    >50  13          b,e! 1,4!diazepin-11-         yl)-(2-pyridin-3-yl-         ethyl)-amine    4    (8-Chloro-5H-dibenzo                     3.0  2.5   5    --          b,e! 1,4!diazepin-11-         yl)-(2-imidazol-1-yl-         ethyl)-amine    5    (8-Chloro-5H-dibenzo                     6.8  4.5   2.5  --         b,e! 1,4!diazepin-11-         yl)-(3-imidazol-1-yl-         propyl)-amine    6    (7-Chloro-5H-dibenzo                     5.5  5.6   50   --          b,e!- 1,4!diazepin-11-         yl)pyridin-3-ylmethyl-         amine    7    (5H-Dibenzo b,e! 1,4!                     23   12    50   >50         diazepin-11-yl)-pyridin-         3-ylmethyl-amine    8    (8-Methyl-5H-dibenzo                     24   31    --   7          b,e! 1,4!diazepin-11-         yl)-pyridin-3-ylmethyl-         amine    9    (8-Methoxy-5H-dibenzo                     27   16    50   >50          b,e! 1,4!diazepin-11-         yl)-pyridin-3-ylmethyl-         amine    10   (8-Bromo-5H-dibenzo b,e!                     6    36          1,4 !diazepin-11-yl)-         pyridin-3-ylmethyl-amine    11   (7,8-Dichloro-5H-dibenzo                     0.8  1.6   50   18          b,e! 1,4!diazepin-11-         yl)-pyridin-3-ylmethyl-         amine    12   (8-Benzyloxy-5H-dibenzo                     >50  37    >50  7          b,e! 1,4!diazepin-11-         yl)-pyridin-3-ylmethyl-         amine    13   (7,8-Dichloro-2,3-                     30   50    --   --         dimethoxy-5H-dibenzo          b,e! 1,4!diazepin-11-         yl)-pyridin-3-ylmethyl-         amine    14   (11H-Benzo b!pyrido                     14   17    50   >50          2,3-e! 1,4!diazepin-5-         yl)-pyridin-3-ylmethyl-         amine    15   (8-Chloro-5-methyl-5H-                     12.2 17    >25  --         dibenzo b,e! 1,4!-         diazepin-11-yl)-pyridin-         3-ylmethyl-amine    16   (8-Chloro-dibenzo b,f!                     9.8  22    --   --          1,4!thiazepin-11-yl)-         pyridin-3-ylmethyl-amine    17   (8-Chloro-5,5-dioxo-5H-                     5.0  6.1   --   --         5λ.sup.6 -dibenzo b,f! 1,4!-         thiazepin-11-yl)-         pyridin-3-ylmethyl-amine    18   (8-Chloro-  8.7  16.5  --   --         dibenzo b,f! 1,4!         oxazepin-11-yl)-pyridin-         3-ylmethyl-amine    __________________________________________________________________________

A compound of Formula Ia ##STR18## wherein X is C--R⁹ wherein R⁹ is asdefined hereinafter or N; R is hydrogen, or alkyl;

n is an integer of 1 to 5;

R¹ is heteroaryl;

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are each independently the same ordifferent and each is hydrogen, NO₂, ##STR19## wherein R¹³ and R¹⁴ areindependently the same or different and each is hydrogen, alkyl, or

R¹³ and R¹⁴ are taken together with N to form a 5- or 6-membered ringoptionally containing a heteroatom selected from the group consisting ofN, S, and O, ##STR20## wherein R¹⁵ is hydrogen, alkyl, or aryl, CO₂ R¹²wherein R¹² is hydrogen, alkyl, or aryl, ##STR21## wherein R¹³ and R¹⁴are as defined above, ##STR22## wherein R¹⁶ is alkyl, aryl, orarylalkyl, halogen, CN, OH, SR¹⁷ wherein R¹⁷ is hydrogen, or alkyl, SOalkyl, SO₂ alkyl, alkoxy, benzyloxy, alkyl, or

substituted alkyl wherein the substituent on the alkyl group is selectedfrom the group consisting of:

OR¹¹ wherein R¹¹ is hydrogen, or alkyl,

SR¹¹ wherein R¹¹ is as defined above,

CO₂ R¹² wherein R¹² is hydrogen, alkyl, or benzyl, ##STR23## wherein R¹³and R¹⁴ are as defined above or, ##STR24## wherein R¹³ and R¹⁴ are asdefined above; with the proviso that at least two of R², R³, R⁴, or R⁹are hydrogen and at least one of R⁵, R⁶, R⁷, or R⁸ is hydrogen;

and corresponding isomers thereof;

or a pharmaceutically acceptable salt thereof may be prepared byreaction of a compound of Formula II ##STR25## wherein X, R², R³, R⁴,R⁵, R⁶, R⁷, and R⁸ are as defined above with a compound of Formula III

    H.sub.2 N--(CH.sub.2).sub.n --R.sup.1                      III

wherein n and R¹ are as defined above in a solvent such as, for example,2-ethoxyethanol and the like at about room temperature to about thereflux temperature of the solvent for about 4 hours to about 30 hours toafford a compound of Formula Ia. Preferably, the reaction is carried outin 2-ethoxyethanol at about reflux for about 30 hours.

A compound of Formula II may be prepared from a compound of Formula IV##STR26## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveby reaction with Lawesson's Reagent,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide!, ina solvent such as, for example, pyridine and the like to afford acompound of Formula II.

A compound of Formula IV may be prepared from a compound of Formula V##STR27## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveby reaction with diphenylphosphoryl azide in a solvent such as, forexample, dimethylformamide and the like and a base such as, for example,triethylamine and the like at about room temperature for about 1 hour toabout 24 hours to afford a compound of Formula IV. Preferably, thereaction is carried out in dimethylformamide and triethylamine at aboutroom temperature for about 24 hours. Alternatively, the reaction may becarried out with N,N'-dicyclohexylcarbodiimide in a solvent such as, forexample, dimethylformamide and the like at about room temperature forabout 24 hours to afford a compound of Formula IV.

A compound of Formula V may be prepared from a compound of Formula VI##STR28## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveby reaction with hydrogen in the presence of a catalyst such as, forexample, Raney nickel and the like in a solvent such as, for example,tetrahydrofuran and the like at about room temperature and a pressure ofabout 50 pounds per square inch (psi) to afford a compound of Formula V.Preferably, the reaction is carried out with Raney nickel intetrahydrofuran at about 50 psi.

A compound of Formula VI may be prepared by reaction of a compound ofFormula VII ##STR29## wherein X, R², R³, and R⁴ are as defined abovewith a compound of Formula VIII ##STR30## wherein R⁵, R⁶, R⁷, and R⁸ areas defined above in the presence of copper (II) acetate in a solventsuch as, for example, isopropanol and the like at about room temperatureto about reflux temperature for about 1 hour to about 24 hours to afforda compound of Formula VI. Preferably, the reaction is carried out inisopropanol at reflux for about 24 hours.

Alternatively, a compound of Formula Ia may be prepared by reaction of acompound of Formula IX ##STR31## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, andR⁸ are as defined above with a compound of Formula III usingconventional methodology to afford a compound of Formula Ia.

A compound of Formula IX may be prepared from a compound of Formula IVin the presence of phosphorus oxychloride using conventional methodologyto afford a compound of Formula IX.

Alternatively, a compound of Formula Ia may be prepared by reaction of acompound of Formula X ##STR32## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, andR⁸ are as defined above using conventional methodology to afford acompound of Formula Ia.

A compound of Formula X may be prepared from a compound of Formula IIand methyl iodide using conventional methodology to afford a compound ofFormula X.

A compound of Formula Ib ##STR33## wherein R¹⁰ is hydrogen, alkyl, or

substituted alkyl wherein the substituent on the alkyl group is selectedfrom the group consisting of:

OR¹¹ wherein R¹¹ is hydrogen, or alkyl,

SR¹¹ wherein R¹¹ is as defined above,

CO₂ R¹² wherein R¹² is hydrogen, alkyl, or benzyl, ##STR34## wherein R¹³and R¹⁴ are independently the same or different and each is hydrogen,alkyl, or

R¹³ and R¹⁴ are taken together with N to form a 5- or 6-membered ringoptionally containing a heteroatom selected from the group consisting ofN, S, and O or ##STR35## wherein R¹³ and R¹⁴ are as defined above, andX, n, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined above may beprepared by reaction of a compound of Formula XI ##STR36## wherein X,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R¹⁰ are as defined above with a compoundof Formula III using methodology previously described for preparing acompound of Formula Ia from a compound of Formula II and a compound ofFormula III to afford a compound of Formula Ib.

A compound of Formula XI is prepared from a compound of Formula XII##STR37## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R¹⁰ are as definedabove using methodology previously described for preparing a compound ofFormula II from a compound of Formula IV to afford a compound of FormulaXI, with the proviso that R¹⁰ cannot contain an amide group when acompound of Formula XII is converted to a compound of Formula XI. Toprepare a compound of Formula XI with R¹⁰ containing an amide group, acompound of Formula XII is prepared with R¹⁰ containing an ester group,for example, an alkyl ester. After converting a compound of Formula XIIto a compound of Formula XI with R¹⁰ containing an ester group, theester group is hydrolyzed to the corresponding acid with a base such as,for example, dilute sodium hydroxide and the like and the correspondingacid converted to the desired amide using conventional mixed anhydridemethodology or carbodiimide methodology.

A compound of Formula XII is prepared from a compound of Formula XIII##STR38## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R¹⁰ are as definedabove using methodology previously described for preparing a compound ofFormula IV from a compound of Formula V to afford a compound of FormulaXII, with the proviso that R¹⁰ cannot contain an amide group when acompound of Formula XIII is converted to a compound of Formula XII. Toprepare a compound of Formula XII with R¹⁰ containing an amide group,one must use the methodology previously described for preparing acompound of Formula XI wherein R¹⁰ contains an amide group.

A compound of Formula XIII is prepared from a compound of Formula XIV##STR39## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R¹⁰ are as definedabove using methodology previously described for preparing a compound ofFormula V from a compound of Formula VI to afford a compound of FormulaXIII.

A compound of Formula XIV is prepared from a compound of Formula XV##STR40## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R¹⁰ are as definedabove by hydrolysis using a base such as, for example, sodium hydroxideand the like in a solvent such as, for example, methanol and the like toafford a compound of Formula XIV. Preferably, the reaction is carriedout with sodium hydroxide in methanol. When R¹⁰ contains an ester group,it is necessary to distinguish this ester from the aromatic esterundergoing hydrolysis on the ring. In this event, the R¹⁰ ester group ispreferably a tertiary butyl ester. After hydrolyzing a compound ofFormula XV with R¹⁰ containing a tertiary butyl ester to a compound ofFormula XIV, a compound of Formula XIV is converted to a compound ofFormula XIII, and then cyclized to a compound of Formula XII andconverted to the thioamide of Formula XI. The tertiary butyl ester inR¹⁰ is then hydrolyzed with an acid such as, for example,trifluoroacetic acid and the like to the corresponding acid and the acidconverted to the desired ester with the BOP reagent(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate)and the corresponding alcohol in a solvent such as, for example,dimethylformamide and the like.

A compound of Formula XV is prepared from a compound of Formula XVI##STR41## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveand a compound of Formula XVII

    R.sup.10 I                                                 XVII

wherein R¹⁰ is as defined above in the presence of a base such as, forexample, sodium hydride and the like in a solvent such as, for example,dimethylformamide and the like to afford a compound of Formula XV.

A compound of Formula Ic ##STR42## wherein Y_(a) is --O-- or --S-- andX, n, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined above isprepared from a compound of Formula XVIII ##STR43## wherein X, Y_(a),R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined above using methodologypreviously described for preparing a compound of Formula Ia from acompound of Formula II and a compound of Formula III to afford acompound of Formula Ic.

A compound of Formula XVIII is prepared from a compound of Formula XIX##STR44## wherein X, Y_(a), R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above using methodology previously described for preparing acompound of Formula II from a compound of Formula IV to afford acompound of Formula XVIII.

A compound of Formula XIX is prepared from a compound of Formula XX##STR45## wherein X, Y_(a), R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above by heating at about 225° C. to afford a compound ofFormula XIX.

A compound of Formula XX is prepared from a compound of Formula XXI##STR46## wherein X, Y_(a), R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above using methodology previously described for preparing acompound of Formula V from a compound of Formula VI to afford a compoundof Formula XX.

A compound of Formula XXI is prepared from a compound of Formula XXII##STR47## wherein X, Y_(a), R², R³, and R⁴ are as defined above and acompound of Formula XXIII ##STR48## wherein R⁵, R⁶, R⁷, and R⁸ are asdefined above in the presence of a base such as, for example, sodiumhydride and the like in a solvent such as, for example,dimethylformamide and the like to afford a compound of Formula XXI.

A compound of Formula Id ##STR49## wherein X, n, R, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are as defined above is prepared from a compound ofFormula XXIV ##STR50## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ asdefined above using methodology previously described for preparing acompound of Formula Ia from a compound of Formula II and a compound ofFormula III to afford a compound of Formula Id.

A compound of Formula XXIV is prepared from a compound of Formula XXV##STR51## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveusing methodology previously described for preparing a compound ofFormula II from a compound of Formula IV to afford a compound of FormulaXXIV.

A compound of Formula XXV is prepared from a compound of Formula XXVI##STR52## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveby reaction with an oxidizing agent such as, for example, hydrogenperoxide and the like in a solvent such as, for example, acetic acid andthe like to afford a compound of Formula XXV.

A compound of Formula Ie ##STR53## wherein X, n, R, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are as defined above is prepared from a compound ofFormula XXVII ##STR54## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above using methodology previously described for preparing acompound of Formula Ia from a compound of Formula II and a compound ofFormula III to afford a compound of Formula Ie.

A compound of Formula XXVII is prepared from a compound of FormulaXXVIII ##STR55## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above using methodology previously described for preparing acompound of Formula II from a compound of Formula IV to afford acompound of Formula XXVII.

A compound of Formula XXVIII is prepared from a compound of Formula XXVIby reaction with an oxidizing agent such as, for example, iodobenzenediacetate and the like in a solvent such as, for example,dimethylformamide and the like to afford a compound of Formula XXVIII.

A compound of Formula If ##STR56## wherein X, n, R, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are as defined is prepared from a compound of Formula Ig##STR57## wherein X, n, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are aboveby reaction with a metal hydride such as, for example, sodiumborohydride and the like in a solvent such as, for example, methanol andthe like to afford a compound of Formula If.

A compound of Formula Ig is prepared from a compound of Formula XXIX##STR58## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveby reaction of the iminochloride of Formula XXIX in ethyleneglycol,diethyl ether in the presence of two equivalents of a compound ofFormula III to afford a compound of Formula Ig.

A compound of Formula XXIX is prepared from a compound of Formula XXX##STR59## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveby reacting a compound of Formula XXX with phosphorus oxychloride in thepresence of N,N,-dimethylaniline to afford a compound of Formula XXIX.

A compound of Formula XXX is prepared from a compound of Formula XXXI##STR60## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveusing methodology previously described for preparing a compound ofFormula XIX from a compound of Formula XX to afford a compound ofFormula XXX.

A compound of Formula XXXI is prepared from a compound of Formula XXXII##STR61## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveusing methodology previously described for preparing a compound ofFormula XIV from a compound of Formula XV to afford a compound ofFormula XXXI.

A compound of Formula XXXII is prepared from a compound of FormulaXXXIII ##STR62## wherein X, R², R³, and R⁴ are as defined above and acompound of Formula XXXIV ##STR63## wherein R⁵, R⁶, R⁷, and R⁸ are asdefined above in the presence of a Lewis acid such as, for example,aluminum chloride and the like in a solvent such as, for example,tetrachloroethane and the like to afford a compound of Formula XXXII.

A compound of Formula Ih ##STR64## wherein X, n, R, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are as defined above is prepared from a compound ofFormula XXXV ##STR65## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above using methodology previously described for preparing acompound of Formula Ia from a compound of Formula II and a compound ofFormula III to afford a compound of Formula Ih.

A compound of Formula XXXV is prepared from a compound of Formula XXXVI##STR66## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined aboveusing methodology previously described for preparing a compound ofFormula II from a compound of Formula IV to afford a compound of FormulaXXXV.

A compound of Formula XXXVI is prepared from a compound of FormulaXXXVII ##STR67## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are asdefined above using N,N'-dicyclohexylcarbodiimide in a solvent such as,for example, dimethylformamide and the like at about room temperaturefor about 24 hours to afford a compound of Formula XXXVI.

A compound of Formula XXXVII is prepared from a compound of Formula XXXIby reaction with hydrazine in the presence of a base such as, forexample, potassium hydroxide and the like in a solvent such as, forexample, ethyleneglycol and the like to afford a compound of FormulaXXXVII.

Compounds of Formula III, Formula VII, Formula VIII, Formula XVI,Formula XVII, Formula XXII, Formula XXIII, Formula XXXIII, and FormulaXXXIV are either known or capable of being prepared by methods known inthe art.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as anticancer agents and as agents to treatrestenosis and psoriasis, and as antiviral agents, the compoundsutilized in the pharmaceutical method of this invention are administeredat the initial dosage of about 1 mg to about 50 mg per kilogram daily. Adaily dose range of about 5 mg to about 25 mg per kilogram is preferred.The dosages, however, may be varied depending upon the requirements ofthe patient, the severity of the condition being treated, and thecompound being employed. Determination of the proper dosage for aparticular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstance isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1 (8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine

A solution of 0.39 g (1.5 mmol) of 8-chloro-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588(1967)) in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.99 mmol)of 3-(aminomethyl)pyridine and heated at reflux for 30 hours. Thesolvent was removed under reduced pressure and the residue mixed withEtOAc and filtered to give 200 mg of the product. The filtrate waschromatographed on silica gel, eluting with EtOAc to give an additional200 mg of product. Total yield 400 mg (80% yield) of the product as ayellow solid, mp 230-234° C. The structure was confirmed by NMR and massspectroscopy. (m+H)⁺ =335.

EXAMPLE 2 (8-Chloro-5H-dibenzo b,e! 1,4!diazepin-11-yl)-2-(3H-imidazol-4-yl)-ethyl!-amine

A solution of 5.8 g (0.022 mol) of 8-chloro-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione in 145 mL of 2-ethoxyethanol was treated with4.94 g (0.044 mol) of histamine and heated at reflux overnight. Thesolvent was removed under reduced pressure and the residue taken up inEtOAc and washed three times with H₂ O, then saturated NaHCO₃ solution,then saturated NaCl solution. Drying over MgSO₄ and removal of thesolvent under reduced pressure left the crude product as a yellow foam.This was dissolved in CH₂ Cl₂ and slowly treated with hexane to give7.44 g (99.2% yield) of the product as an amorphous yellow solid. Thestructure was confirmed by NMR and mass spectroscopy. (m+H)⁺ =338.

EXAMPLE 3 (8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(2-pyridin-3-yl-ethyl)-amine

A solution of 0.5 g (1.9 mmol) of 8-chloro-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione in 10 mL of 2-ethoxyethanol was treated with 0.46g (3.8 mmol) of 3-(2-aminoethyl)pyridine and heated at reflux overnight.The solvent was removed under reduced pressure and the residue taken upin EtOAc and washed five times with H₂ O, then saturated NaCl solution.Drying over MgSO₄ and removal of the solvent under reduced pressure gavethe crude product. Recrystallization from acetone/water gave 0.49 g (74%yield) of the product as a yellow solid, mp 195-196° C. The structurewas confirmed by NMR and mass spectroscopy. (m+H)⁺ =349.

EXAMPLE 4 (8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(2-imidazol-1-yl-ethyl)-amine

A solution of 0.6 g (2.3 mmol) of 8-chloro-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione in 15 mL of 2-ethoxyethanol was treated with 0.6mL (4.6 mmol) of 1-(2-aminoethyl)imidazole and heated at reflux for 2days. The solvent was removed under reduced pressure and the residuetaken up in EtOAc and washed three times with H₂ O, then saturatedNaHCO₃ solution, and saturated NaCl solution. Drying over MgSO₄ andremoval of the solvent under reduced pressure left the crude product.This was recrystallized from EtOAc/hexane using charcoal to give 0.44 g(57.1% yield) of the product as pale yellow crystals, mp 168-170° C. Thestructure was confirmed by NMR and mass spectroscopy. (m+H)⁺ =338.

EXAMPLE 5 (8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(3-imidazol-1-yl-propyl)-amin

A solution of 0.6 g (2.3 mmol) of 8-chloro-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione in 15 mL of 2-ethoxyethanol was treated with 0.6mL (4.6 mmol) of 1-(3-aminopropyl)imidazole and heated at reflux for 3days. The solvent was removed under reduced pressure and the residuetaken up in EtOAc and washed four times with H₂ O, then saturated NaHCO₃solution, and saturated NaCl solution. Drying over MgSO₄ and removal ofthe solvent under reduced pressure left the crude product. Triturationwith EtOAc/hexane followed by recrystallization from acetone/water gave506 mg (62.6% yield) of the pure product as a golden solid, mp 228-230°C. The structure was confirmed by NMR and mass spectroscopy. (m+H)⁺=352.

EXAMPLE 6 (7-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine

A solution of 0.41 g (1.57 mmol) of 7-chloro-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588(1967)) in 10 mL 2-ethoxyethanol was treated with 0.32 mL (3.14 mmol) of3-(aminomethyl)pyridine and heated at reflux for 22 hours. The solventwas removed under reduced pressure and the residue mixed with EtOAc andfiltered to give 0.31 g of product. The filtrate was concentrated andchromatographed on silica gel, eluting with EtOAc to give an additional0.16 g of product. The material was combined and recrystallized fromEtOAc/hexane to give 0.3 g (56.6% yield) of the product as a pale yellowsolid, mp 218-220° C. The structure was confirmed by NMR and massspectroscopy. (m+H)⁺ =335.

EXAMPLE 7 (5H-Dibenzo b,e! 1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 0.6 g (2.7 mmol) of 5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione German Patent, DE-2,306,762, C.A. 79:126533a(1973)! in 10 mL 2-ethoxyethanol was treated with 0.6 mL (5.4 mmol) of3-(aminomethyl)pyridine and heated at reflux overnight. The solvent wasremoved under reduced pressure and the residue taken up in EtOAc andwashed three times with H₂ O, then saturated NaHCO₃ solution andsaturated NaCl solution. Drying over MgSO₄ and removal of the solventunder reduced pressure left the crude product. Chromatography on silicagel, eluting with CHCl₃ /MeOH (95/5) gave the product. On adding CH₂Cl₂, the product crystallized. There was obtained 459 mg (58.1% yield)of the pure product as a yellow solid, mp 150-152° C. The structure wasconfirmed by NMR and mass spectroscopy. (m+H)⁺ =301.

EXAMPLE 8 (8-Methyl-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 0.32 g (1.3 mmol) of 8-methyl-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588(1967)) in 10 mL 2-ethoxyethanol was treated with 0.3 mL (2.9 mmol) of3-(aminomethyl)pyridine and heated at reflux overnight. The solvent wasremoved under reduced pressure and the residue taken up in EtOAc andwashed two times with H₂ O, then saturated NaHCO₃ solution and saturatedNaCl solution. Drying over MgSO₄ and removal of the solvent underreduced pressure left the crude product. Recrystallization fromEtOAc/hexane gave 0.2 g (50% yield) of the pure product as a lightyellow solid, mp 186-187° C. The structure was confirmed by NMR and massspectroscopy. (m+H)⁺ =315.

EXAMPLE 9 (8-Methoxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 0.25 g (0.98 mmol) of 8-methoxy-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588(1967)) in 10 mL of 2-ethoxyethanol was treated with 0.22 mL (2.1 mmol)of 3-(aminomethyl)pyridine and heated at reflux overnight. The solventwas removed under reduced pressure and the residue taken up in EtOAc andwashed three times with H₂ O, then saturated NaHCO₃ solution andsaturated NaCl solution. Drying over MgSO₄ and removal of the solventunder reduced pressure left the crude product. Chromatography on silicagel, eluting with a gradient of CH₂ Cl₂ /hexane (80/20) to CH₂ Cl₂ /MeOH(94/6) gave 80 mg (25% yield) of the product as a yellow solid, mp160-161° C. The structure was confirmed by NMR and mass spectroscopy.(m+H)⁺ =331.

EXAMPLE 10 (8-Bromo-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 0.4 g (1.3 mmol) of 8-bromo-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione (Sahni, S., et al., J. Indian Chem. Soc., 56:625(1979)) in 10 mL of 2-ethoxyethanol was treated with 0.28 mL (2.1 mmol)of 3-(aminomethyl)-pyridine and heated at reflux overnight. The solventwas removed under reduced pressure and the residue taken up in EtOAc andwashed three times with H₂ O, then saturated NaHCO₃ solution andsaturated NaCl solution. Drying over MgSO₄ and removal of the solventunder reduced pressure left the crude product. Trituration with CH₂ Cl₂/hexane, then with Et₂ O/hexane left 0.3 g (61% yield) of the product asa yellow solid, mp 152-155° C. The structure was confirmed by NMR andmass spectroscopy. (m+H)⁺ =379.

EXAMPLE 11 (7,8-Dichloro-5H-dibenzo b,e!1,4!diazepin-11yl)-pyridin-3-ylmethyl-amine

Step a. Preparation of: 7,8-Dichloro-10,11-dihydro-5H-dibenzob,e!-1,4-diazepin-11-thione

A solution of 492 mg (1.8 mmol) of 7,8-dichloro-5,10-dihydro-dibenzob,e! 1,4!diazepin-11-one (Giani R. P., et al., Synthesis, 550 (1985)) in7 mL pyridine was treated with 0.9 g (2.1 mmol) of Lawesson's Reagentand heated at reflux overnight. The solvent was removed under reducedpressure. The residue was mixed with dilute HCl and a little acetone,then diluted with EtOAc. The EtOAc was washed with 1N HCl, H₂ O,saturated NaHCO₃ solution, and saturated NaCl solution. Drying overMgSO₄ and removal of the solvent under reduced pressure left the crudeproduct. This was taken up in EtOAc, treated with charcoal, filtered,and the solvent removed under reduced pressure. The residue wasrecrystallized from acetone/H₂ O to give 329 mg (63.3% yield) of ayellow solid, mp 235-260° C. (d). The structure was confirmed by massspectroscopy. (m+H)⁺ =296.

Step b. Preparation of: (7,8-Dichloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 329 mg (1.1 mmol) of 7,8-dichloro-5,10-dihydro-dibenzob,e! 1,4!diazepin-11-thione in 10 mL of 2-ethoxyethanol was treated with0.3 mL (2.2 mmol) of 3-(aminomethyl)pyridine and heated at refluxovernight. The solvent was removed under reduced pressure and theresidue taken up in EtOAc and washed three times with H₂ O, thensaturated NaHCO₃ solution and saturated NaCl solution. Drying over MgSO₄and removal of the solvent under reduced pressure left the crudeproduct. Chromatography on silica gel, eluting with CHCl₃ /MeOH (97/3)followed by recrystallization from acetone/H₂ O gave 217 mg (52.8%yield) of the product as a yellow solid, mp 209-210° C. The structurewas confirmed by NMR and mass spectroscopy. (m+H)⁺ =370.

EXAMPLE 12 (8-Benzyloxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

Step a. Preparation of: N-(2-Nitro-4-benzyloxyphenyl)anthranilic acid

Under nitrogen, a solution of 5.5 g (16.1 mmol) ofdiphenyliodonium-2-carboxylate, monohydrate, 3.6 g (14.6 mmol) of2-nitro-4-benzyloxyaniline, and 0.4 g Cu(OAc)₂ in 50 mL of isopropanolwas heated at reflux overnight. The mixture was poured into H₂ O andacidified with dilute HCl. The solid was collected, taken up in EtOAc,and treated with charcoal. The solvent was removed under reducedpressure and the residue recrystallized from EtOAc/hexane to give 2.19 g(41.3% yield) of the product as a red-brown solid, mp 227-229° C. (d).The structure was confirmed by mass spectroscopy. (m+H)⁺ =365.

Step b. Preparation of: N-(2-Amino-4-benzyloxyphenyl)anthranilic acid

A solution of 2.17 g (6.0 mmol) ofN-(2-nitro-4-benzyloxyphenyl)anthranilic acid in 100 mL THF was treatedwith 1.5 g Raney nickel and reduced with hydrogen at 25° C., 50 psi. Themixture was filtered and the solvent removed under reduced pressureleaving 1.95 g (97.9% yield) of the product as a tan solid. Thestructure was confirmed by mass spectroscopy. (m+H)⁺ =335.

Step c. Preparation of: 8-Benzyloxy-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-one

A solution of 1.95 g (5.8 mmol) ofN-(2-amino-4-benzyloxyphenyl)anthranilic acid in 75 mL DMF was treatedwith 1.6 mL (7.0 mmol) of diphenylphosphoryl azide and 1.8 mL (12.8mmol) of Et₃ N and allowed to stir at room temperature overnight. Thesolution was diluted with H₂ O and the pH brought to Congo red end pointwith dilute HCl. The mixture was extracted twice with EtOAc and thecombined EtOAc washed three times with H₂ O, then saturated NaHCO₃solution and saturated NaCl solution. Drying over MgSO₄ and removal ofthe solvent under reduced pressure left a dark oil. Chromatography onsilica gel, eluting with CHCl₃, gave the product. Recrystallization fromacetone/H₂ O gave 1.19 g (64.7% yield) of the pure product as an orangesolid, mp 154-156° C. The structure was confirmed by NMR and massspectroscopy. (m+H)⁺ =317.

Step d. Preparation of: 8-Benzyloxy-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione

A solution of 1.17 g (3.7 mmol) of 8-benzyloxy-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-one in 15 mL pyridine was treated with 1.8 g (4.4 mmol)of Lawesson's Reagent and heated at reflux overnight. The solvent wasremoved under reduced pressure and the residue mixed with dilute HCl anda little acetone. The mixture was diluted with EtOAc and washed with 1NHCl, H₂ O, saturated NaHCO₃ solution, and saturated NaCl solution.Drying over MgSO₄ and removal of the solvent under reduced pressure leftthe crude product. This was taken up in EtOAc, treated with charcoal,and the solvent removed under reduced pressure. The residue wasrecrystallized from acetone/H₂ O to give 0.95 g (77.9% yield) of theproduct as a golden solid, mp 203-205° C. The structure was confirmed bymass spectroscopy. (m+H)⁺ =333.

Step e. Preparation of: 8-Benzyloxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 0.6 g (1.8 mmol) of 8-benzyloxy-5,10-dihydro-dibenzo b,e!1,4!diazepin-11-thione in 10 mL 2-ethoxyethanol was treated with 0.4 mL(3.6 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight.The solvent was removed under reduced pressure and the residue taken upin EtOAc and washed three times with H₂ O, then with saturated NaHCO₃solution and saturated NaCl solution. Drying over MgSO₄ and removal ofthe solvent under reduced pressure gave the crude product. Aftertrituration with CHCl₃ /hexane, recrystallization from MeOH gave 349 mg(47.8% yield) of the product as a yellow solid, mp 196-197° C. Thestructure was confirmed by NMR and mass spectroscopy. (m+H)⁺ =407.

EXAMPLE 13 (7,8-Dichloro-2,3-dimethoxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

Step a. Preparation of:2-(2-Amino-4,5-dichlorophenylamino)-4,5-dimethoxy-benzoic acid

Under nitrogen, a solution of 5.36 g (16.2 mmol) of2-iodo-4,5-dimethoxybenzoic acid, sodium salt in 50 mL DMF was treatedwith 2.9 g (16.2 mmol) of 2-amino-4,5-dichloroaniline, 0.2 g Cu(OAc)₂,and 1.8 mL (16.2 mmol) of N-methylmorpholine and heated at reflux for 4hours. The mixture was poured into H₂ O and acidified with 16.2 mL (32.4mmol) of 2N HCl. The mixture was extracted with EtOAc and the EtOAcwashed three times with H₂ O, then with saturated NaCl solution. Dryingover MgSO₄ and removal of the solvent under reduced pressure left thecrude product as a black oil. Mixing with CH₂ Cl₂ /hexane gave a solidwhich was recrystallized from acetone/H₂ O to give 596 mg (11.7% yield)of a yellow solid, mp 210-212° C. (d). The structure was confirmed bymass spectroscopy. (m+H)⁺ =358.

Step b. Preparation of: 7,8-Dichloro-2,3-dimethoxy-5,10-dihydro-dibenzob,e! 1,4!diazepin-11-one

A solution of 595 mg (1.7 mmol) of2-(2-amino-4,5-dichlorophenylamino)-4,5-dimethoxy-benzoic acid in 20 mLDMF was treated with 0.6 mL (3.7 mmol) of Et₃ N and 0.42 mL (2.0 mmol)of diphenylphosphoryl azide and allowed to stir at room temperatureovernight. The solution was poured into H₂ O and acidified to the Congored end point with dilute HCl. A solid was collected which wastriturated with CH₃ CN/MeOH to give 359 mg (64.1% yield) of the productas a pale yellow solid, mp 297-300° C. (d). The structure was confirmedby mass spectroscopy. (m+H)⁺ =340.

Step c. Preparation of: 7,8-Dichloro-2,3-dimethoxy-5,10-dihydro-dibenzob,e! 1,4!diazepin-11thione

A solution of 359 mg (1.1 mmol) of7,8-dichloro-2,3-dimethoxy-5,10-dihydro-dibenzo b,e! 1,4!diazepin-11-onein 10 mL pyridine was treated with 0.53 g (1.3 mmol) of Lawesson'sReagent and heated at reflux overnight. The solvent was removed underreduced pressure and the residue mixed with dilute HCl and a littleacetone. The mixture was diluted with EtOAc and washed with 1N HCl, twotimes with H₂ O, saturated NaHCO₃ solution, and saturated NaCl solution.Drying over MgSO₄ and removal of the solvent under reduced pressure gavethe crude product. Trituration with CH₂ Cl₂ /hexane gave 305 mg (82.4%yield) of the product as an orange solid, mp 279-281° C. (d). Thestructure was confirmed by mass spectroscopy. (m+H)⁺ =356.

Step d. Preparation of: 7,8-Dichloro-2,3-dimethoxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 302 mg (0.9 mmol) of7,8-dichloro-2,3-dimethoxy-5,10-dihydro b,e! 1,4!diazepin-11-thione in15 mL of 2-ethoxyethanol was treated with 0.36 mL (3.6 mmol) of3-(aminomethyl)pyridine and heated at reflux for 3 days. The solvent wasremoved under reduced pressure and the residue taken up in EtOAc andwashed three times with H₂ O, then with saturated NaHCO₃ solution andsaturated NaCl solution. Drying over MgSO₄ and removal of the solventunder reduced pressure left the crude product. Chromatography on silicagel, eluting with CHCl₃ /MeOH (95/5) gave 250 mg (69.4% yield) of theproduct as a golden solid foam. The structure was confirmed by NMR andmass spectroscopy. (m+H)⁺ =430.

EXAMPLE 14 (11H-Benzo b!pyrido 2,3-e!1,4!diazepin-5-yl)-pyridin-3-ylmethyl-amine

A solution of 0.5 g (2.2 mmol) of 6,11-dihydro-5H-pyrido 2,3-b!1,5!benzodiazepin-5-thione (European Published Patent ApplicationEP-393,604); C.A. 114, 143455! in 10 mL 2-ethoxyethanol was treated with0.24 mL (10.8 mmol) of 3-(aminomethyl)pyridine and heated at reflux for2 days. The mixture was poured into H₂ O and extracted with EtOAc. TheEtOAc was washed three times with H₂ O, then saturated NaHCO₃ solutionand saturated NaCl solution. Drying over MgSO₄ and removal of thesolvent under reduced pressure left the crude product. Chromatography onsilica gel, eluting with a gradient of CH₂ Cl₂ /hexane (90/10) to CH₂Cl₂ /MeOH (94/6) gave 0.35 g (53% yield) of the product as a yellowsolid, mp 192-194° C. The structure was confirmed by NMR and massspectroscopy. (m+H)⁺ =302.

EXAMPLE 15 (8-Chloro-5-methyl-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 329 mg (1.2 mmol) of8-chloro-5-methyl-5,10-dihydro-dibenzo b,e! 1,4!diazepin-11-thione(Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL of2-ethoxyethanol was treated with 0.3 mL (2.4 mmol) of3-(aminomethyl)pyridine and heated at reflux overnight. The solvent wasremoved under reduced pressure and the residue taken up in EtOAc andwashed three times with H₂ O, then saturated NaHCO₃ solution andsaturated NaCl solution. Drying over MgSO₄ and removal of the solventunder reduced pressure left the crude product as an oil. Chromatographyon silica gel, eluting with CHCl₃ /MeOH (98/2) gave 160 mg (38.4% yield)of the product as a golden solid foam. The structure was confirmed byNMR and mass spectroscopy. (m+H)⁺ =349.

EXAMPLE 16 (8-Chloro-dibenzo b,f!1,4!thiazepin-11-yl-pyridin-3-ylmethyl-amine

A solution of 682 mg (2.5 mmol) of 8-chlorodibenzob,f!-1,4-thiazepin-11(10H)-thione (Polivka Z., et al., Coll. Czech.Chem. Comm., 48:1465 (1983)) in 15 mL of 2-ethoxyethanol was treatedwith 0.5 mL (5.0 mmol) of 3-(aminomethyl)pyridine and heated at refluxovernight. The solvent was removed under reduced pressure and theresidue taken up in EtOAc and washed three times with H₂ O, thensaturated NaHCO₃ solution and saturated NaCl solution. Drying over MgSO₄and removal of the solvent under reduced pressure left the crudeproduct. Chromatography on silica gel, eluting with CHCl₃ /MeOH (98/2)following by recrystallization from CHCl₃ /hexane gave 600 mg (69.8%yield) of the product as a white solid, mp 152-153° C. The structure wasconfirmed by NMR and mass spectroscopy. (m+H)⁺ =352.

EXAMPLE 17 (8-Chloro-5,5-dioxo-5H-5λ⁶ -dibenzo b,f!1,4!thiazepin-11-yl)-pyridin-3-ylmethyl-amine

Step a. Preparation of: 8-Chloro-5,5-dioxo-dibenzob,f!-1,4-thiazepin-11(10H)-one

A suspension of 0.91 g (3.5 mmol) of 8-chloro dibenzob,f!-1,4-thiazepin-11(10H)-one in 100 mL HOAc was warmed to 90° C. toeffect solution, and the hot solution was treated over 2 hours with 10mL of 30% H₂ O₂. The solution was then allowed to stand at roomtemperature for 3 days. A solid separated and was washed with H₂ O togive 526 mg (51.6% yield) of the product, mp >300° C. The structure wasconfirmed by mass spectroscopy. (m+H)⁺ =294.

Step b. Preparation of: 8-Chloro-5,5-dioxo-dibenzob,f!-1,4-thiazepin-11(10H)-thione

A solution of 507 mg (1.7 mmol) of 8-chloro-5,5-dioxo-dibenzob,f!-1,4-thiazepin-11(10H)-one in 15 mL pyridine was treated with 0.88 g(2.1 mmol) of Lawesson's Reagent and heated at reflux overnight. Thesolvent was removed under reduced pressure and the residue treated withdilute HCl and a little acetone. The material was taken up in EtOAc andwashed with 1N HCl, two times with H₂ O, saturated NaHCO₃ solution, andsaturated NaCl solution. Drying over MgSO₄ and removal of the solventunder reduced pressure gave the crude product. Since thin layerchromatography showed a mixture of product and starting material, thecrude product was re-treated with Lawesson's Reagent and refluxed for 3days. Work-up as above gave 0.46 g (86.8% yield) of the product as agolden solid, mp 255-260° C. (d). The structure was confirmed by massspectroscopy. (m+H)⁺ =310.

Step c. Preparation of: (8-Chloro-5,5-dioxo-5H-5λ⁶ -dibenzo b,f!1,4!thiazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 0.46 g (1.5 mmol) of 8-chloro-5,5-dioxo-dibenzob,f!-1,4-thiazepin-11(10H)-thione in 15 mL of 2-ethoxyethanol wastreated with 0.3 mL (3.0 mmol) of 3-(aminomethyl)pyridine and heated atreflux overnight. An additional 0.4 mL of 3-(aminomethyl)pyridine wasadded and the refluxing continued another night. The solvent was removedunder reduced pressure and the residue taken up in EtOAc and washedthree times with H₂ O, then saturated NaHCO₃ solution and saturated NaClsolution. Drying over MgSO₄ and removal of the solvent under reducedpressure left the crude product. Chromatography on silica gel, elutingwith CHCl₃ /MeOH (97/3) followed by precipitating the product fromacetone with H₂ O gave an amorphous tan solid. The structure wasconfirmed by NMR and mass spectroscopy. (m+H)⁺ =384.

EXAMPLE 18 (8-Chloro-dibenzo b,f!1,4!oxazepin-11-yl)-pyridin-3-ylmethyl-amine

A solution of 706 mg (2.7 mmol) of 8-chlorodibenzob,f!-1,4-oxazepin-11(10H)-thione (Nagarajan K., et al., Indian J. Chem.,12:258 (1974)) in 20 mL of 2-ethoxyethanol was treated with 0.6 mL (5.4mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. Thesolvent was removed under reduced pressure and the residue taken up inEtOAc and washed three times with H₂ O, then saturated NaHCO₃ solutionand saturated NaCl solution. Drying over MgSO₄ and removal of thesolvent under reduced pressure left the crude product. Chromatography onsilica gel, eluting with CHCl₃ /MeOH (98/2) followed byrecrystallization from CH₂ Cl₂ /hexane gave 436 mg (48.1% yield) of theproduct as a cream solid, mp 167-169° C. The structure was confirmed byNMR and mass spectroscopy. (m+H)⁺ =336.

We claim:
 1. A compound of Formula I ##STR68## wherein X is C--R⁹,wherein R⁹ is as defined hereinafter or N; Y is ##STR69## wherein R¹⁰ ishydrogen, alkyl, or substituted alkyl wherein the substituent on thealkyl group is selected from the group consisting of:OR¹¹ wherein R¹¹ ishydrogen, or alkyl, SR¹¹ wherein R¹¹ is as defined above, CO₂ R¹²wherein R¹² is hydrogen, alkyl, or benzyl, ##STR70## wherein R¹³ and R¹⁴are independently the same or different and each is hydrogen, alkyl, orR¹³ and R¹⁴ are taken together with N to form a 5- or 6-membered ringoptionally containing a heteroatom selected from the group consisting ofN, S, and O, or ##STR71## wherein R¹³ and R¹⁴ are as defined above,--CH₂ --, --O--, --S(O)_(m) -- wherein m is zero or an integer of 1 or2, ##STR72## or R is hydrogen, or alkyl; n is an integer of 1 to 5; R¹is heteroaryl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are each independentlythe same or different and each is hydrogen, NO₂, ##STR73## wherein R¹³and R¹⁴ are as defined above, ##STR74## wherein R¹⁵ is hydrogen, alkyl,or aryl, CO₂ R¹² wherein R¹² is as defined above, ##STR75## wherein R¹³and R¹⁴ are as defined above, ##STR76## wherein R¹⁶ is alkyl, aryl, orarylalkyl, halogen, CN, OH, SR¹⁷ wherein R¹⁷ is hydrogen, or alkyl, SOalkyl, SO₂ alkyl, alkoxy, benzyloxy, alkyl, orsubstituted alkyl whereinthe substituents on the alkyl group are as defined above; with theproviso that at least two of R², R³, R⁴, or R⁹ are hydrogen and at leastone of R⁵, R⁶, R⁷, or R⁸ is hydrogen; and corresponding isomers thereof;or a pharmaceutically acceptable salt thereof.
 2. A compound accordingto claim 1 wherein R¹ is a heteroaryl radical selected from the groupconsisting of:2- or 3-thienyl; 2- or 3-furanyl; 1-, 2-, or 3-pyrrolyl;1-, 2-, 4-, or 5-imidazolyl; 1-, 3-, 4-, or 5-pyrazolyl; 2-, 4-, or5-thiazolyl; 3-, 4-, or 5-isothiazolyl; 2-, 4-, or 5-oxazolyl; 3-, 4-,or 5-isoxazolyl; 1-, 2-, 4-, or 5-1,2,3-triazolyl; 1- or 5-tetrazolyl;4- or 5-1,2,3-oxadiazolyl; 3- or 5-1,2,4-oxadiazolyl;2-1,3,4-oxadiazolyl; 2-1,3,4-thiadiazoyl; 2-1,3,5-triazinyl;3-pyridinyl; 3-, 4-, or 5-pyridazinyl; 2-pyrazinyl; and 2-, 4-, or5-pyrimidinyl; oroptionally, the heteroaryl radical is substituted witha substituent selected from the group consisting of: NH₂, OH, SH,halogen, alkyl, or alkoxy.
 3. A compound according to claim 2 whereinYis --NH--, ##STR77## --O--, --S--, or --SO₂ --; n is an integer of 1 to5; R¹ is a heteroaryl radical selected from the group consisting of:1-,2-, or 4-imidazolyl, 3-pyridinyl, 1-, 3-, or 5-1,2,4-triazolyl,5-thiazolyl, or 5-oxazolyl; R³ and R⁴ are hydrogen or alkoxy; R⁶ and R⁷arehydrogen, halogen, mercaptomethyl, hydroxymethyl, alkoxy, alkyl, orbenzyloxy.
 4. A compound according to claim 3 selected from the groupconsisting of:(8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)pyridin-3-ylmethyl-amine; (8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)- 2-(3H-imidazol-4-yl)-ethyl!-amine;(8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(2-pyridin-3-yl-ethyl)-amine; (8-Chloro-5H-dibenzob,e! 1,4!diazepin-11-yl)-(2-imidazol-1-yl-ethyl)-amine;(8-Chloro-5H-dibenzo b,e!1,4!diazepin-11-yl)-(3-imidazol-1-yl-propyl)-amine; (7-Chloro-5H-dibenzob,e! 1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine; (5H-Dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine; (8-Methyl-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine; (8-Methoxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine; (8-Bromo-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine; (7,8-Dichloro-5H-dibenzob,e! 1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine;(8-Benzyloxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine;(7,8-Dichloro-2,3-dimethoxy-5H-dibenzo b,e!1,4!diazepin-11-yl)-pyridin-3-ylmethyl-amine; (11H-Benzo b!pyrido 2,3-e!1,4!diazepin-5-yl)-pyridin-3-ylmethyl-amine;(8-Chloro-5-methyl-5H-dibenzo b,e!1,4!diazepin-11yl)-pyridin-3-ylmethyl-amine; (8-Chloro-dibenzo b,f!1,4!thiazepin-11-yl)-pyridin-3-ylmethyl-amine;(8-Chloro-5,5-dioxo-5H-5λ⁶ -dibenzo b,f!1,4!thiazepin-11-yl)-pyridin-3-ylmethyl-amine; and (8-Chloro-dibenzob,f! 1,4!oxazepin-11-yl)-pyridin-3-ylmethyl-amine.
 5. A method oftreating tissue proliferative diseases comprising administering to ahost suffering therefrom a therapeutically effective amount of acompound according to claim 1 in unit dosage form.
 6. A method oftreating ras-related cancer comprising administering to a host sufferingtherefrom a therapeutically effective amount of a compound according toclaim 1 in unit dosage form.
 7. A method of treating restenosiscomprising administering to a host suffering therefrom a therapeuticallyeffective amount of a compound according to claim 1 in unit dosage form.8. A method of treating psoriasis comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 9. A method of treatingprenyl-related viral infections comprising administering to a hostsuffering therefrom a therapeutically effective amount of a compoundaccording to claim 1 in unit dosage form.
 10. A pharmaceuticalcomposition comprising a compound according to claim 1 in admixture witha pharmaceutically acceptable excipient, diluent, or carrier.
 11. Apharmaceutical composition adapted for administration as anantiproliferative agent comprising a therapeutically effective amount ofa compound according to claim 1 in admixture with a pharmaceuticallyacceptable excipient, diluent, or carrier.
 12. A pharmaceuticalcomposition adapted for administration as an anticancer agent, orrestenosis inhibiting agent or antipsoriasis agent or antiviral agentcomprising a therapeutically effective amount of a compound according toclaim 1 in admixture with a pharmaceutically acceptable excipient,diluent, or carrier.
 13. A method for preparing a compound having theFormula Ia ##STR78## wherein X is C--R⁹ wherein R⁹ is as definedhereinafter or N; R is hydrogen, or alkyl;n is an integer of 1 to 5; R¹is heteroaryl; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are each independentlythe same or different and each is hydrogen, NO₂, ##STR79## wherein R¹³and R¹⁴ are independently the same or different and each is hydrogen,alkyl, or R¹³ and R¹⁴ are taken together with N to form a 5- or6-membered ring optionally containing a heteroatom selected from thegroup consisting of N, S, and O, ##STR80## wherein R¹⁵ is hydrogen,alkyl, or aryl, CO₂ R¹² wherein R¹² is hydrogen, alkyl, or benzyl,##STR81## wherein R¹³ and R¹⁴ are as defined above, ##STR82## whereinR¹⁶ is alkyl, aryl, or arylalkyl, halogen, CN, OH, SR¹⁷ wherein R¹⁷ ishydrogen, or alkyl, SO alkyl, SO₂ alkyl, alkoxy, benzyloxy, alkyl,orsubstituted alkyl wherein the substituent on the alkyl group isselected from the group consisting of: OR¹¹ wherein R¹¹ is hydrogen, oralkyl, SR¹¹ wherein R¹¹ is as defined above, CO₂ R¹² wherein R¹² ishydrogen, alkyl, or benzyl, ##STR83## wherein R¹³ and R¹⁴ are as definedabove, or ##STR84## wherein R¹³ and R¹⁴ are as defined above; with theproviso that at least two of R², R³, R⁴, or R⁹ are hydrogen and at leastone of R⁵, R⁶, R⁷, or R⁸ is hydrogen;and corresponding isomers thereof;or a pharmaceutically acceptable salt thereof comprises reaction of acompound of Formula II ##STR85## wherein X, R², R³, R⁴, R⁵, R⁶, R⁷, andR⁸ are as defined above with a compound of Formula III

    H.sub.2 N--(CH.sub.2).sub.n --R.sup.1                      III

wherein n and R¹ are as defined above in a solvent to afford a compoundof Formula 1a and, if desired, converting a compound of Formula Ia to acorresponding pharmaceutically acceptable salt by conventional meansand, if so desired, converting the corresponding pharmaceuticallyacceptable salt to a compound of Formula Ia by conventional means.